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Original Contribution |

Systemic Metabolic Abnormalities in Adult-onset Acid Maltase Deficiency:  Beyond Muscle Glycogen Accumulation

Juan M. Pascual, MD, PhD; Charles R. Roe, MD
JAMA Neurol. 2013;70(6):756-763. doi:10.1001/jamaneurol.2013.1507.
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Importance The physiological relevance of acid maltase (acid α-glucosidase, an enzyme that degrades lysosomal glycogen) is well recognized in liver and muscle. In late (adult)–onset acid maltase deficiency (glycogen storage disease type II [GSD II]), glycogen accumulates inside muscular lysosomes in the context of reduced enzymatic activity present not only in muscle, but also throughout the organism. Yet, disease manifestations are commonly attributed to lysosomal disruption and autophagic vesicle buildup inside the myofiber due to a lack of obvious hepatic or broader metabolic dysfunction. However, current therapies primarily focused on reducing glycogen deposition by dietary or enzyme replacement have not been consistently beneficial, providing the motivation for a better understanding of disease mechanisms.

Objective To provide a systematic overview of metabolism and methylation capacity using widely available analytical methods by evaluating secondary compromise of (1) the citric acid cycle, (2) methylation capacity, and (3) nutrient sensor interaction in as many as 33 patients with GSD II (ie, not all patients were available for all assessments) treated with only a low-carbohydrate/high-protein, calorie-balanced diet.

Design, Setting, and Patients Case series including clinical and analytical characterization in an academic setting involving 33 enzymatically proved adults with GSD II treated only with a low-carbohydrate/high-protein, calorie-balanced diet.

Main Outcome and Measure Biochemical analysis of blood and urine samples.

Results Patients exhibited evidence for disturbed energy metabolism contributing to a chronic catabolic state and those who were studied further also displayed diminished plasma methylation capacity and elevated levels of insulin-like growth factor type 1 and its carrier protein insulin-like growth factor binding protein 3 (IGFBP-3).

Conclusions and Relevance The simplest unifying interpretation of these abnormalities is nutrient sensor disturbance with secondary energy failure leading to a chronic catabolic state. Data also provide the framework for the investigation of potentially beneficial interventions, including methylation supplementation, as adjuncts specifically targeted to ameliorate the systemic metabolic abnormalities of this disorder.

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Figure 1. Urinary citrate levels from late-onset patients with glycogen storage disease type II. A, Urine levels from 19 untreated patients with glycogen storage disease type II compared with controls (reference upper limit, 803 mmol/mol creatinine). B, Urine citrate at baseline and 7 months later in 4 untreated patients illustrating the intermittent nature of excessive urine citrate levels.

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Figure 2. Plasma insulin-like growth factor type 1 (IGF-1) (A) and insulin-like growth factor binding protein 3 (IGFBP-3) (B) levels from 26 untreated patients with glycogen storage disease type II (gray bars) compared with 164 healthy participants (open bars) distributed by age ranges. The levels for both IGF-1 and IGFBP-3 were significantly elevated for the late-onset patients with glycogen storage disease type II at all age ranges indicating potentially impaired intracellular transfer of IGF-1. To convert IGF-1 to nanomoles per liter, multiply by 0.131.

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Figure 3. Acute response to a triheptanoin meal over 6 hours by insulin-like growth factor type 1 (IGF-1) (A) and urine citrate (B) levels. The decrease of IGF-1 suggests increased intracellular uptake, possibly related to increased adenosine triphospate availability. The rapid decline of urinary citrate is consistent with enhanced metabolism of citrate, potentially due to enhanced adenosine triphospate production and inactivation of adenosine monophosphate–activated protein kinase. To convert IGF-1 to nanomoles per liter, multiply by 0.131.

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Figure 4. Schematic of the integrated methylation pathways. Blue font represents metabolites that accumulate and red font denotes those whose concentration decreases as observed with patients with glycogen storage disease type II. ADP indicates adenosine diphosphate; AGAT, L-arginine:glycine amidinotransferase; ATP, adenosine triphosphate; CK, creatinine kinase; GAA, guanidinoacetate; GAMT, guanidinoacetate N-methyltransferase; MS, methionine synthase; MTHF, methyltetrahydrofolate; SAH, S -adenosylhomocysteine; SAM, S -adenosylmethionine; and THF, tetrahydrofolate.

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